19-Hydroxy-13,14-dihydro-PG2 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-13,14-dihydro-PG 2  compounds methods for their preparation and pharmacological use for the induction of prostaglandin-like effect.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a division of Ser. No. 025,899, filed Apr. 2,1979 now U.S. Pat. No. 4,228,104.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandin analogs.Particularly, these compounds are analogs of the prostaglandins whereinthe C-19 position is substituted by hydroxy, i.e., 19-hydroxy-PGcompounds. Most particularly, the present invention relates to novel19-hydroxy-13,14-dihydro-PG₂ compounds, a disclosure of the preparationand use of which is incorporated here by reference from U.S. Pat. No.4,228,104.

PRIOR ART

Prostaglandin analogs exhibiting hydroxylation in the 19-position areknown in the art. See, for example, U.S. Pat. No. 4,127,612, Sih, J. C.,Prostaglandins 13:831 (1977) and U.S. Pat. Nos. 3,657,316, 3,878,046,and 3,922,297. See also the additional references cited in U.S. Ser. No.025,899.

SUMMARY OF THE INVENTION

The present invention particularly provides:

A compound of the formula ##STR1## wherein D is (1) cis--CH═CH--CH₂--(CH₂)_(g) --CH₂ --,

(2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,

wherein g is zero, one, two, or three;

wherein Q is α-OH:β-R₅ or α-R₅ :β-OH,

wherein R₅ is hydrogen or methyl,

wherein R₆ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3 carbon atoms, inclusive; ##STR2## wherein (p-Ph) is para-phenyl orinter-para-phenylene, and R₂₈ is phenyl, p-bromophenyl, p-biphenylyl,

p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation;

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same ordifferent, with the proviso that one of R₃ and R₄ is fluoro only whenthe other is hydrogen or fluoro;

wherein W is oxo, methylene, α-OH:β-H, or α-H:β-OH; and wherein X is--CH₂ CH₂ --.

With regard to the divalent the substituents described above (e.g., Q)these divalent radicals are defined as α-R_(I) :β-R_(J), wherein R_(I)represents the substituent of the divalent moiety in the alphaconfiguration with respect to the ring and R_(J) represents thesubstituent of the divalent moiety in the beta configuration withrespect to the plane of the ring. Accordingly, when Q is defined asα-OH:β-R₅, the hydroxy of the Q moiety is in the alpha configuration,i.e., as in the natural prostaglandin, and the R₅ substituent is in thebeta configuration.

Specific embodiments of the present invention include:

19(R)-19-hydroxy-13,14-dihydro-PGF₂α, p-acetylphenyl ester.

The compounds of the present invention are particularly useful forinducing prostaglandin-like biological effects, as is described in theU.S. Ser. No. 025,899. Uses of compounds in accordance with the presentinvention include, therefore, anti-asthmatic indications.

I claim:
 1. A compound of the formula ##STR3## wherein D is (1)cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --,(2) cis--CH═CH--CH₂ --(CH₂)_(g)--CF₂ --,wherein g is zero, one, two, or three; wherein Q is α-OH:β-R₅or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl,wherein R₆ is (a)hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkylof 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms,inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloroor alkyl groups of one to 3 carbon atoms, inclusive; ##STR4## wherein(p-Ph) is para-phenyl or inter-para-phenylene, and R₂₈ is phenyl,p-bromophenyl, p-biphenylyl,p-nitrophenyl, p-benzamidophenyl, or2-naphthyl, or (o) a pharmacologically acceptable cation; wherein R₂ ishydrogen, hydroxyl, or hydroxymethyl; wherein R₃ and R₄ are hydrogen,methyl, or fluoro, being the same or different, with the proviso thatone of R₃ and R₄ is fluoro only when the other is hydrogen orfluoro;wherein W is oxo, methylene, α-OH:β-H, or α-H:β-OH; and wherein Xis --CH₂ CH₂ --.
 2. 19(R)-19-Hydroxy-13,14-dihydro-PGF₂α, p-acetylphenylester, a compound according to claim 1.